Food intolerances are a common complaint, of which gluten sensitivity is one of the most common and serious. It has 2 distinct manifestations, Celiac Disease (CD) and Dermatitis Herpetiformis (DH), which affect 1% of the population, a number that has increased several folds over recent decades. Gluten sensitivity is currently treated by a very restrictive diet avoiding wheat, rye, and barley, and foods containing ingredients from these grains. Both CD and DH are associated with certain common genes encoding HLA DQ2 and HLA DQ8;however, only certain individuals carrying these genes will develop an unchecked immune response to wheat-derived gluten while most people with these genes do not develop CD or DH, despite lifelong exposure to gluten. These diseases, even when clinically silent, are associated with excess mortality and morbidity. These diseases can occur at any time in life, either early with the first exposure to gluten, which may be due to a lack of development of tolerance to gluten, or later in life, which may be due to an apparent loss of tolerance to gluten. The broad, long-term objectives of this application are to determine the immunological processes that contribute to the development or loss of tolerance to gluten, an increasingly common problem. Knowledge gained from these studies will be later used to develop both preventative measures and curative therapies for both celiac disease and dermatitis herpetiformis patients, thereby achieving the mission of the NIH in extending their lives and reducing the substantial burden of these diseases. Research Design and Methods/Specific Aims: The first aim of this proposal is to examine (using novel mouse models of gluten sensitivity) how the different combinations of these genes affect the development of gluten sensitivity and thereby identify which combinations of genes are most likely to result in gluten sensitive enteropathy. The next aim will be to use the mouse models of gluten sensitivity to determine the immunological processes that occur when factors (both genetic and environmental) associated with childhood in CD and DH, such as gastrointestinal infections, disrupt the development of immunological tolerance to gluten. The third aim outlines how we would determine the mechanisms that lead to immunological intolerance to gluten later in life. This would be achieved by mimicking (in our mouse model) known events that have been associated with the development of either CD or DH late in life.